Polymer composition for implant manufacture

Abstract

The present invention is directed to a method for manufacturing a bioresorbable polymeric medical implant and a polymeric composition for use in such a method. The inventive polymer blend comprises a PCL / PLA mixture in solution, and further comprises a compatibilizer. The inventive method comprises producing the inventive polymeric composition, and using said polymeric composition to form the selected implant, followed by heat treatment.

Description

[0001] F07418 03.12.2025

[0002] 1

[0003] TITLE

[0004] POLYMER COMPOSITION FOR IMPLANT MANUFACTURE

[0005] TECHNICAL FIELD

[0006] The present invention relates to a method for manufacturing a bioresorbable polymeric medical implant, especially a stent, based on a polymer composition comprising PCL and PLA, as well as such a polymer composition, a method for producing such a polymer composition, and an implant manufactured therefrom.

[0007] PRIOR ART

[0008] Aortic valvular disease (AVD) is one of the major causes of morbidity and mortality1 2with 300,000 to 400,000 patients undergoing heart valve replacement worldwide every year34. Aortic valve repair and / or replacement are options for patients suffering from insufficiency and severe stenosis, respectively. Currently, surgical aortic valve replacement is considered the gold standard treatment option with a mechanical or a bioprosthetic valve as a substitute56. Mechanical valves are mostly used in patients under 65 years of age, due to their durability and freedom from re-operation secondary to valvular degeneration7. However, they induce high shear stresses on the blood, causing hemolysis and blood coagulation8, thus making a lifelong anticoagulation treatment necessary9. On the other hand, bioprosthetic valves based on fixed biological tissue show good physiological hemodynamics but have limited durability due to progressive degeneration and lack of selfrepair or growth capacity. Lately, transcatheter aortic valve implantation (TAVI) has been developed as an alternative method to the surgical approach. Due to its minimally-invasive nature, TAVI is a suitable procedure for high-, intermediate-, and now also low-risk patients10. However, the loss of valve functionality consequent to bioprosthetic tissue degradation is particularly accelerated in younger patients, leading to several reinterventions throughout their lives, further increasing the risk of morbidity and mortality11. Next-generation tissue- engineered heart valve (TEHV) replacements with regenerative capacities have demonstrated their strong potential in numerous preclinical and first-clinical pilot studies12and may represent an ideal candidate to overcome the limitations of current prostheses. Recently, TEHVs were further merged with the latest minimally-invasive implantation technologies13. Here, the valves are sewn onto a collapsible and re-expandable nitinol stent and crimped down to very small diameters to finally be delivered in the heart by means of F07418 03.12.2025

[0009] 2 transcatheter approaches14’15.

[0010] Stent devices are crucial for successful valve implantation, delivery, and structural support after deployment. Ideally, stents should act as a supportive element to the implanted heart valve until their full integration into the host tissue, after which their presence is no longer needed16. In this regard, pediatric patients necessitate a rapidly adapting stent, which size and diameter grow together with the native annulus, while simultaneously possessing sufficient mechanical properties and degrading while being replaced by surrounding host tissue. Nowadays, metal stents are commonly used for TAVI, but they lack growth and remodeling capacities, thereby causing long-term drawbacks, such as hyperplasia, thrombosis, and infections17’18. To solve these problems, bioabsorbable polymers can be used as starting materials for stent fabrication19. These materials are suitable due to their short-term presence, low rate of thrombus formation, and compatibility with minimally invasive techniques20. Additionally, these materials may fulfill several criteria suitable for heart valve application, such as limited plastic deformation, durable positioning after deployment, and sufficient radial forces21.

[0011] Bioabsorbable polymers including polylactic acid (PLA), polyglycolic acid (PGA), and polycaprolactone (PCL), and their blends are gaining popularity in the fabrication of various stents22 23. The properties of these polymers are of interest due to their suitable mechanical strength, bioresorbable ability, and degradation time24-26. Ongoing research focuses on tailoring the mechanical properties of PLA and PCL and their blends with other polymers to enhance their suitability for diverse applications, especially in the medical field27'30.

[0012] Significant progress has been made in the utilization of polymeric blend materials in the manufacturing of medical devices, especially with the addition of biodegradable polymers such as PCL and PLA33. These materials are becoming increasingly popular because of their special mix of qualities that meet the demanding requirements of medical applications. PCL and PLA are members of the aliphatic polyester family, which are both biocompatible and biodegradable and, therefore can be used in temporary medical devices that are implanted within the human body34’35. PCL having a low melting point and high elongation at break proves itself to be flexible and easily processable, while PLA owing to its high glass transition temperature offers high tensile strength36’37. Mixing these polymers creates a blend polymer resulting in a material that can be tailored to specific mechanical and degradation requirements38’39.

[0013] The fabrication of heart valve stents using a shape memory PCL / PLA blend represents a significant advancement in the field of medical devices30’40. The biodegradability of these polymers is particularly advantageous, as it allows the stent to provide temporary support to the heart valve and degrade over time, eliminating the need for a second surgical F07418 03.12.2025

[0014] 3 procedure41. By adjusting the ratio of PCL to PLA, the degradation rate of the stent can be fine-tuned to match the healing process of the tissue, ensuring that the stent remains functional for the required duration42-44. Moreover, PCL / PLA blends offer a balance of flexibility and mechanical strength, essential for stents that must navigate through the heart and withstand the dynamic forces within the body45. The bio- and hemocompatibility of these materials minimize the risk of inflammation, blood clotting, and other adverse reactions, promoting better integration with the host tissue4647.

[0015] There is a need for a self-expandable polymeric stent, especially a heart valve stent, which has bioresorbable capacities, overcomes key limitations of current metallic stents, and is compatible with minimally invasive technologies, i.e. is crimpable. It is especially desirable to achieve the manufacture of an implant that displays a favorable combination of mechanical strength, biodegradability, and biocompatibility, including hemocompatibility. The mechanical strength shall be sufficient to provide temporary structural support, while its degradation rate shall comply with the requirements for gradual tissue integration.

[0016] SUMMARY OF THE INVENTION

[0017] Such a desired bioresorbable polymeric medical implant, preferably a stent, more preferably a vascular, valvular, or tracheal stent, most preferably a cardiovascular stent, such as a heart valve stent, can be manufactured by a method according to claim 1. In said method, the implant is formed from a polymer composition according to claim 5, namely a homogenized PCL / PLA blend, obtainable by a method according to claim 11.

[0018] The inventive method for manufacturing a bioresorbable polymeric medical implant, preferably a stent, more preferably a vascular, valvular, or tracheal stent, most preferably a heart valve stent, comprises the following steps: a.) mixing of PCL and PLA, at a PCL / PLA weight ratio in a range of from 60:40 to 85: 15, preferably in a range of from 70:30 to 80:20, more preferably at a PCL / PLA weight ratio of 75:25 (weight%, w / w), resulting in a "PCL / PLA mixture". Preferably, the PCL / PLA mixture contains PCL in powder form and PLA in granular form. b.) dissolving the PCL / PLA mixture resulting from step a.) in a solvent, resulting in a "PCL / PLA solution". The solvent used preferably is a volatile solvent, more preferably a volatile organic solvent. According to an especially preferred embodiment, the solvent is selected from a group consisting of 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (hexafluoroisopropanol, HFIP), trifluoroethanol (TFE), dimethyl sulfoxide (DMSO), F07418 03.12.2025

[0019] 4 dichloromethane (DCM), and chloroform. Most preferably, the solvent is HFIP. The solvent is preferably added to the PCL / PLA mixture up to a concentration of 40-80% (w / v), more preferably up to a concentration of 50-70% (w / v), most preferably up to a concentration of about 60% (w / v) of the PCL / PLA mixture in the PCL / PLA solution. c.) adding a compatibilizer to the PCL / PLA solution resulting from step b.), resulting in a "PCL / PLA blend". The compatibilizer promotes homogeneity and improves the miscibility of polymer blends, as it reduces the interfacial tension between two phases, forms a finer dispersed phase, enhances the morphological stability against coalescence and enhances domain adhesion in a poorly miscible polymer blend. The compatibilizer is preferably added at a concentration in a range of 3-8% (w / w), more preferably of 4-7% (w / w), most preferably at a concentration of about 5% (w / w) with respect to the weight of the PCL / PLA mixture resulting from step a.). In an especially preferred embodiment of the present invention, the compatibilizer is a PCL / PLA copolymer, preferably comprising a lactide:caprolactoneratio in the range of 15:85 to 40:60, more preferably of 30:70, most preferably of 35:65 (w / w). Most preferably, the compatibilizer is poly(L-lactide-co-caprolactone) (PLCL). d.) agitating the PCL / PLA blend resulting from step c.), preferably by sonication, resulting in a "homogenized PCL / PLA blend". Ideally, the homogenized PCL / PLA blend is indeed homogenous, i.e. no particles are visible by eye in the homogenized blend after the agitation step. Preferably, the sonication is carried out at a power of about 20W and a frequency of about 20kHz, however, this can be adjusted individually. e.) forming the homogenized PCL / PLA blend to a precursor implant body according to a selected implant design, resulting in a precursor implant body. The precursor implant body can be viewed as a "green body", which in general already has reached its overall form, but still needs to be submitted to further manufacturing or processing steps, in order to reach its final properties. Preferably, the green body refers to a "wet" body, which still has to be dried in a later step. f.) submitting the precursor implant body resulting from step e.) to a heat treatment at 60-120°C, and at a pressure exceeding atmospheric pressure, resulting in a casted, dried implant body. During the heat-treatment, the solvent evaporates and the material of the precursor implant body is stabilized. The resulting casted, dried implant body is preferably "solvent-free”. This is important to avoid toxicity following implantation, as is mandatory for clinical applications. g.) cooling of the dried implant body resulting from step f.), preferably at least to room temperature, resulting in a bioresorbable polymeric medical implant.

[0020] The cooling step g.) can be an active cooling step, such as in a refrigerator or on ice. F07418 03.12.2025

[0021] 5

[0022] However, and more preferably, the dried implant body, after its removal from the device, in which it was heat treated, such as in a reactor, an oven, or a heated pressure pot, the implant body is simply left to cool off gradually at room temperature without any active intervention, i.e. letting the dried implant body to a "passive", natural cooling process. This ensures uniform and gradual cooling off.

[0023] In step e.), the precursor implant body is preferably formed by using the homogenized PCL / PLA blend as an ink resulting from step d.) in a 3D printing process based on the selected implant design. Therein, the precursor implant body is preferably formed by depositing the homogenized PCL / PLA blend on a scaffold. The scaffold, ideally serves as a removable scaffold for the precursor implant body which is removed after the cooling step, e.g. by dissolving in water. In case the implant to be manufactured is a stent, the scaffold preferably is a rotating mandrel. According to a preferred embodiment, the scaffold itself can be the product of a 3D printing process. In 3D printing, the implant is preferably formed based on a G-code defining the selected implant design.

[0024] Alternatively to 3D printing, the homogenized PCL / PLA blend can be used as an injection molding substrate, a spinning substrate, or a dip-coating substrate in the manufacturing of the bioresorbable polymeric medical implant.

[0025] The heat treatment of step f.) is preferably carried out at 80-100°C, more preferably at about 90°C. The heat treatment is preferably carried out at a pressure 1-3 bar, more preferably at 1.5-2.5 bar, and most preferably at about 2 bar. Advantageously, the heat and / or the pressure is gradually increased up to the desired respective value. The heat treatment is preferably carried out for 8-30 hours, more preferably for 12-24 hours. Preferably, after forming, the precursor implant body is placed in a pressure pot for the purpose of curing.

[0026] Optionally, further post-processing steps, such as sterilization, lyophilization, fitting, etc. can be carried out on the bioresorbable polymeric medical implant, if desired, prior to implantation.

[0027] The initial combination of PCL and PLA resulting from step a.) is termed a "mixture" before the addition of the compatibilizer PLCL. Once the preferred compatibilizer is added, which helps to increase the miscibility, and subsequently to reduce phase separation, the composition is termed a "blend." After agitation, the blend is termed a "homogenized blend", as is it at least visually homogenous. Microscopically, the level of homogeneity depends on the concentration of the compatibilizer. Different concentrations of the compatibilizer result in varying degrees of homogeneity and reduced phase separation, especially after heat F07418 03.12.2025

[0028] 6 treatment.

[0029] The present invention furthermore is directed to a bioresorbable polymeric medical implant, preferably a stent, which is manufactured by a method as described above. The bioresorbable polymeric stent offers significant potential in congenital heart disease, where vessel growth and anatomical variability demand adaptable and degradable support structures. Unlike metallic frames that restrict somatic growth and necessitate repeated interventions, the bioresorbable polymeric stent according to the present invention gradually resorbs as the native tissue remodels, thereby reducing the need for re-dilation or surgical exchange. The use of the inventive PCL / PLA polymer composition furthermore enables tailored mechanical compliance and geometry for pediatric anatomies, allowing personalized interventions in conditions such as branch pulmonary artery stenosis or right ventricular outflow tract obstruction. This approach directly addresses one of the major unmet needs in pediatric cardiology, creating a temporary yet functional scaffold that supports vessel patency while accommodating natural growth.

[0030] However, a stent according to present invention, has a broad applicability, not limited to the cardiovascular system (including all types of vessels) and heart valve stents. The stent thus can be any hollow organ stent (including, e.g. trachea and bronchus, esophagus, prostate, bile duct, and others, where maintaining an open passageway is critical, such as in cases of cancer. More preferably, the stent is a vascular, or valvular or tracheal stent, most preferably a heart valve stent.

[0031] The same bioresorbable polymeric stent concept can be applied to the venous system, particularly for restoring valve function and maintaining lumen patency in chronic venous insufficiency and post-thrombotic syndrome. In deep vein thrombosis (DVT), thrombus formation and subsequent fibrosis often lead to valve destruction and outflow obstruction. A biodegradable stent according to the present invention, and incorporating a venous valve could re-establish unidirectional flow, prevent reflux, and promote endogenous valve regeneration while the stent gradually resorbs. This temporary support strategy reduces the long-term risks associated with permanent metallic implants, such as thrombosis, migration, or mechanical mismatch, and provides a regenerative solution for patients with severe DVT- induced venous obstruction.

[0032] Advantageously, the stent according to the present invention is self-expandable. This refers to the intrinsic ability of a stent to expand to its predetermined size upon deployment, without requiring external forces such as balloon inflation. This characteristic is a critical feature for ensuring functionality and adaptability in medical applications. PCL and PLA were selected for implant fabrication partly because of their inherent shape memory characteristics. The F07418 03.12.2025

[0033] 7 use of these materials renders the stent capable of recovering their original diameter after the temporary deformation applied to it during implantation (crimping). Neither the addition of a compatibilizer nor the subsequent heat treatment have any observable effect on the shape memory behavior of the PCL / PLA blend. The method of production also influences and impacts self-expandability.

[0034] The present invention is also directed to a polymer composition, for use in the manufacture of a bioresorbable polymeric medical implant, comprising a solution containing a mixture of polycaprolactone (PCL) and polylactic acid (PLA), the polymer composition further comprising a compatibilizer, characterized in that a PCL / PLA weight ratio in the PCL / PLA mixture is in a range of from 60:40 to 85:15, preferably in a range of from 70:30 to 80:20, wherein the PCL / PLA weight ratio most preferably is 75:25. The compatibilizer is contained in the polymer composition according to the present invention at a concentration of less than 10% (w / w) with respect to the weight of the PCL / PLA mixture. The homogenized PCL / PLA blend produced according to the method mentioned above represents the inventive polymer composition. Such an inventive polymer composition can be produced by a method comprising steps a.)-d.) as described above, thus being part of the method for manufacturing the bioresorbable polymeric medical implant.

[0035] The concentration of the PCL / PLA mixture in the solution is in a range of 40-80% (w / v), preferably of 50-70% (w / v), more preferably of 55-65% (w / v), wherein the concentration of the PCL / PLA mixture in the solution most preferably is about 60% (w / v).

[0036] The solvent is preferably selected from a group consisting of 1 ,1 , 1 ,3,3, 3-hexafluoro-2- propanol (hexafluoroisopropanol, HFIP), trifluoroethanol (TFE), dimethyl sulfoxide (DMSO), dichloromethane (DCM), and chloroform, wherein the solvent most preferably is HFIP.

[0037] In the polymer composition according to the present invention and used for the manufacture of the bioresorbable polymeric medical implant, the compatibilizer is a PCL / PLA copolymer, preferably poly(L-lactide-co-caprolactone) (PLCL), more preferably comprising a lactide: caprolactone ratio in the range of from 15:85 to 40:60, more preferably of 30:70, most preferably of 35:65 weight percent (%w / w).

[0038] In a particularly preferred embodiment of the present invention, the compatibilizer is contained in the polymer composition at a concentration of 3-8% (w / w), preferably of 4-7% (w / w), more preferably of 4.5-6% (w / w), most preferably of about 5% (w / w) with respect to the weight of the PCL / PLA mixture.

[0039] By fine-tuning the composition of the polymer blend, i.e. the PCL / PLA weight ratio and the weight ratio of the solvent and the compatibilizer, it is possible to individually tailor the F07418 03.12.2025

[0040] 8 degradation rate or timeline according to the purpose of the implant application. Types of stents requiring a faster degradation, where presumably a higher PLA content is necessary, including at least, among others, coronary artery drug-eluting stents, pediatric airway stents (tracheobronchial stents), cardiovascular stents for congenital heart defects, biliary stents (temporary biliary stents), Ureteral Stents (For kidney stone relief), bronchial stents for bronchomalacia, pancreatic duct stents, esophageal stents, (for palliative treatment), colonic stents (for temporary relief). On the other hand, types of stents requiring a slower degradation where presumably a higher PCL content is necessary, include at least, among others, structural heart valve stents, peripheral arterial stents, (femoral or popliteal artery stents), and gastrointestinal stents (for long-term colonic patency). The above-described method thus is also applicable to the manufacture of at least these further types of implants.

[0041] Steps a.)-d.) as described above in the method / process for manufacturing a bioresorbable polymeric medical implant, represent the steps for producing a polymer composition suitable for the manufacture of a bioresorbable polymeric medical implant. The present invention is thereby also directed to a method for producing a polymer composition suitable for the manufacture of a bioresorbable polymeric medical implant comprising at least the above-described steps a.)-d.).

[0042] The method for manufacturing a bioresorbable polymeric medical implant thus first comprises the manufacture of the inventive polymer composition, namely the homogenized PCL / PLA blend, by carrying out steps a.)-d.), followed by steps e.)-g.) for the forming of the bioresorbable polymeric medical implant from said polymer composition. However, the method for manufacturing a bioresorbable polymeric medical implant can also be expressed by providing a polymer composition as described above, i.e. the homogenized PCL / PLA blend, such as in cases when it is obtained in a ready-to-use form, followed by steps e.)-g.) for the forming of the bioresorbable polymeric medical implant from said polymer composition.

[0043] The present invention furthermore extends to a polymer composition, i.e. a homogenized PCL / PLA blend suitable for the manufacture of a bioresorbable polymeric medical implant, preferably of a stent, wherein the polymer composition is obtained by a method comprising steps a.)-d.) as described above.

[0044] The above-mentioned polymer composition, preferably obtained by a method comprising the above-described steps a.)-d.), i.e. the described homogenized PCL / PLA blend, for use F07418 03.12.2025

[0045] 9 in the manufacturing of a bioresorbable polymeric medical implant, can be used, as mentioned above as an ink for 3D-printing of the bioresorbable polymeric medical implant, or as an injection molding substrate, a spinning substrate, or a dip-coating substrate in the manufacturing of the bioresorbable polymeric medical implant. The present invention thus also extends to the use of the polymer composition, i.e. in form of the described homogenized PCL / PLA blend, and preferably obtained by a method comprising steps a.)- d.) as described above, as an ink in a 3D-printing process of a bioresorbable polymeric medical implant, or as an injection molding-, a spinning-, or a dip-coating substrate for the manufacture of a bioresorbable polymeric medical implant.

[0046] The present invention furthermore is directed to a bioresorbable polymeric medical implant, preferably a stent, more preferably a vascular, valvular, or tracheal stent, most preferably a cardiovascular stent, such as a heart valve stent, which is formed from / of the polymer composition as described above, wherein the bioresorbable polymeric medical implant preferably is formed from / of the polymer composition obtained or obtainable by a method comprising steps a.)-d.) as described above.

[0047] The term "forming an implant" can comprise the step of applying the homogenized PCL / PLA blend to a mold representing the desired form of the implant, or onto a scaffold. The homogenized PCL / PLA blend can for example be placed in a syringe, via which the homogenized PCL / PLA blend is then applied either to a 3D printer nozzle or alternatively directly onto a scaffold. The form can be tailored to specific anatomical features / design of the desired implant.

[0048] The present invention is based on an in vitro developmental process and in vivo validation of a self-expandable polymeric heart valve stent that has bioresorbable capacities and is compatible with minimally invasive technologies. With respect to previous transcatheter TEHVs, a novel method is presented to manufacture an implant formed from a blend of PCL and PLA, which was defined and systematically characterized by macroscopic and microscopic analyses, Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), mechanical test, biodegradability, biocompatibility, and hemocompatibility. A 3D-printer with a single rotational axis was then used to print a crimpable, biodegradable polymeric medical stent. The in vivo performance of the novel polymeric stent was verified in a porcine model.

[0049] Further embodiments of the invention are laid down in the dependent claims. F07418 03.12.2025

[0050] 10

[0051] BRIEF DESCRIPTION OF THE DRAWINGS

[0052] Preferred embodiments of the invention are described in the following with reference to the drawings, which are for the purpose of illustrating the present preferred embodiments of the invention and not for the purpose of limiting the same. In the drawings,

[0053] Fig. 1 shows in A.)-F) a detailed photographic representation of a fabrication process of a polymeric stent according to a preferred embodiment of the present invention;

[0054] Fig. 2 shows a photographic representation of a stent delivery device comprising, as shown in A.), a customized 3D printed valve housing (white) and a valve transferring tool (brown) (scale bar: 20mm), wherein B.) shows a view along the longitudinal axis of a stent inside the valve housing, and (C) shows a detailed view along the longitudinal axis of the transferring tool having a wire hole;

[0055] Fig. 3 shows a table with information on the stents and animals used for the in-vivo study;

[0056] Fig. 4 shows a table representing microscopic images of polymer blend samples: without heat treatment, with heat treatment, and with heat treatment in combination with the PLCL compatibilizer;

[0057] Fig. 5 shows representative SEM images of a sample cross-section, wherein in A.), a sheet sample produced from a PCL / PLA (75:25) blend without heat treatment and in B), a sheet sample subjected to heat treatment is shown;

[0058] Fig. 6 shows in A) results of an FTIR analysis of various PCL / PLA blends with different concentrations of PCL and PLA, and in (B) DSC test results showing Tg and Tm of the different PCL / PLA blends;

[0059] Fig. 7 shows a table representing the results of a tensile test, wherein the Young's Modulus (E, MPa) of different tested samples prepared from polymer blends with different PCL / PLA ratios are shown, without heat treatment, with only heat treatment, and with heat treatment in combination with compatibilizer, and the values of the latter group of samples after 4 months of biodegradation in PBS (wherein the values represent the mean ± SD, n = 3);

[0060] Fig. 8 shows the evaluation of assays for the assessment of biocompatibility, biodegradation and thrombin generation, respectively, of samples prepared from the different PCL / PLA blends, wherein in 8A.), the results are shown for F07418 03.12.2025

[0061] 11 human dermal fibroblasts (hDFs), wherein in 8B.) the results for human umbilical vein endothelial cells (HLIVEC) are shown; wherein 8C.) reflects the biodegradation of the samples prepared from the different PCL / PLA blends after 1-4 months in PBS at 37 °C; and wherein in 8D.) results of a thrombin generation assay (TGA) are shown (LDPE: Low-density Polyethylene (minimal reactive); PDMS: Polydimethylsiloxane (intermediary reactive); MS: Medical Steel (highly reactive); therein, the values represent the mean ± SD, n = 3, *p < .05, **p < .01 , and ***p < .001 (SD: standard deviation));

[0062] Fig. 9 shows the results of the evaluation of polymeric stent biodegradation under dynamic conditioning, in order to compare samples produced from a PCL / PLA (75:25) blend with and without bismuth oxychloride 20% up to 6 months;

[0063] Fig. 10 shows a comparison of mechanical properties of non-crimpable and crimpable stents;

[0064] Fig. 11 shows results of a cell proliferation assay of dermal fibroblast cells on a stent produced from a PCL / PLA (75:25) blend containing BiCIO 20%;

[0065] Fig. 12 shows results of a Thrombin generation assay (TGA) for a stent produced from a PCL / PLA (75:25) blend containing BiCIO 20% (LDPE: Low-density Polyethylene (minimal reactive), PDMS: Polydimethylsiloxane (intermediary reactive), MS: Medical Steel (highly reactive));

[0066] Fig. 13 shows mechanical properties of a crimpable stent produced from a PCL / PLA (75:25) blend containing BiCIO 20%.

[0067] DESCRIPTION OF PREFERRED EMBODIMENTS

[0068] In the present study, an improved PCL / PLA blend was prepared using HFIP as a volatile organic solvent due to its high solvating power for both PCL and PLA and its rapid evaporation4849. As a result of this property, the formation of air vesicles within the PCL / PLA samples was observed. To avoid a dramatic impact on the polymer's mechanical properties, the air vesicles were promptly removed via a heat treatment under high-pressure conditions. However, as PCL and PLA are not miscable, a phenomenon of phase separation occurred. Phase separation refers to the process where two polymers segregate into distinct regions rather than forming a uniform mixture, which can affect the material's overall properties and performance50. Thus, PLCL was used as a compatibilizer, thereby reducing the size of the dispersed particles (specifically PCL) and stabilizing the blend morphology at processing, consequently increasing the toughness of the PCL / PLA blend51’52. Results from a Fourier- F07418 03.12.2025

[0069] 12

[0070] Transformation Infrared Spectroscopy (FTIR) analysis prove the absence of solution residue on the PCL / PLA blend, as well as of the compatibilizer, since the characteristic peaks of HFIP and PLCL do not appear on the spectra of PCL / PLA blends and present a similar peak distribution, compared with pure PLA and PCL. This means there are no new functional groups that appeared in PCL / PLA blends53. The DSC results of composites and pure PCL and PLA show that the glass transition temperature (Tg) of the PCL / PLA composites increases slightly with increasing PLA content. This is because the higher melting temperature of PLA and semi-crystalline PCL molecular chains can affect the crystallization process of PLA54. In addition, PCL serves as the soft segment due to its low melting temperature of around 70 °C, while PLA, with a higher melting point of approximately 140 °C, acts as the hard segment53. Since the mechanical properties of the inventive polymer blend can be significantly enhanced through the application of the heat treatment and the compatibilizer, the Young's modulus of the respective material was measured. The polymer stiffness showed a considerable increase due to the enhanced crystallinity of the polymer after heat treatment and due to the incorporation of PLCL. Moreover, the experimental data demonstrated a direct correlation between PLA content and material stiffness, supporting the DSC results, which indicate PLA as the hard segment. However, the presence of the compatibilizer and the subsequent heat treatment ensures that the inherent flexibility of PCL is not entirely compromised, resulting in a material that is both strong and durable. By comparing the present results with previous studies, the significant impact of the compatibilizer and heat treatment on the mechanical properties of PCL / PLA blends becomes evident. For instance, Ma et al. reported Young's modulus of approximately 125 MPa for a PCL / PLA (50 / 50) blend55. In contrast, the present study demonstrated a significant improvement, with Young's modulus for the same blend ratio measured at 317.57 ± 14.68 MPa without heat treatment and compatibilizer. This value further increased to 438.48 ± 18.84 MPa after the application of heat treatment and the incorporation of a compatibilizer.

[0071] Blending biodegradable polymers is a well-known technique for modifying their degradation rate56, which is an essential parameter for designing bioresorbable cardiovascular implants. The present results demonstrated that PLA and composites with higher PLA content exhibited a faster degradation rate and loss of mechanical properties, particularly during the last two months of the study. This is attributed to PLA's high hydrophilicity and its molecular structure, which contains more amorphous regions compared to PCL57’58. The higher hydrophilicity of PLA facilitates greater water uptake, accelerating hydrolytic degradation. Additionally, the amorphous regions in PLA degrade more rapidly than the crystalline regions found predominantly in PCL, contributing to the observed faster degradation. The F07418 03.12.2025

[0072] 13 present findings are supported by existing literature, which documents similar biodegradation rates after four months55’59. These findings also align with Li et al., who found that increasing PLA content in polymer blends accelerates degradation but compromises mechanical integrity over time. The PCL / PLA balance is therefore crucial, as it ensures that the material degrades appropriately within the body without compromising its functionality during the critical initial period of implantation. Insights into the biocompatibility and cellular response to the blended PCL / PLA samples showed that both hDFs and HUVECs exhibited robust proliferation across all sample types. Notably, there was a marked increase in cell proliferation with higher PLA content. This is likely attributable to PLA's lower hydrophobicity compared to PCL, which enhances cell attachment and proliferation, an important aspect for applications such as cardiovascular stents, where rapid endothelialization is necessary to prevent thrombosis and ensure proper function. These findings are consistent with previous studies that have demonstrated the positive impact of hydrophilic surfaces on cell adhesion and proliferation62. Similarly, based on the obtained hemocompatibility results, the maximum thrombin generation for the PCL, PCL / PLA (75:25), and PLA samples was significantly lower than that of medical steel and comparable to LDPE. This indicates that the preferred PCL / PLA (75:25) blend has excellent hemocompatibility, making it highly suitable for cardiovascular applications.

[0073] Additive manufacturing has emerged as a highly promising production method for polymeric heart valve stents, which are intended to be bioresorbable and have shape memory properties. This technique allows for the precise control of stent geometry and enables the customization of stent designs to match the anatomical requirements of individual patients63. Among others, printing on a rotational axis 3D-printer ensures optimal alignment of the stent struts and provides excellent control over the stent's diameter and wall thickness, which are critical for its mechanical performance and deployment in cardiovascular applications64. For the present study, a 3D-printer with a single rotational axis was adopted as the preferred method for fabricating polymeric stents, as it combines the advantages of customization, precision, and compatibility with the unique requirements of bioresorbable polymeric stents. The use of a 3D-printer with a single rotational axis (i.e. a 4-axis 3D- printer) resulted in the formation of continuous polymer fibres along the length of the stent, as compared to discontinuous fibres, as would have been the case if a standard 3-axis 3D- printer had been used. The precision of 3D-printing ensures control over material structure and distribution of the PCL / PLA blend (ink), thus preserving the shape memory properties crucial for the important feature of self-expandability of the stent. After the printing process, the polymeric stent radial forces were measured to evaluate its mechanical performance. In this study, the standard metallic stent served as the gold standard, exhibiting a TRF of F07418 03.12.2025

[0074] 14

[0075] 79.1 N and a radial load of 2.6 N / mm. While these values confirm its clinical efficacy, the results demonstrate that polymeric stents offer superior performance, particularly the zigzag and one-cell designs. The zig-zag stent, with a TRF of 98.5 N and a radial load of 4 N / mm, outperformed the one-cell stent, which had a higher TRF of 132.8 N but a less balanced combination of flexibility and strength. The zig-zag stent's design appears to distribute the applied load more effectively, maintaining structural integrity while also providing the necessary flexibility, making it a promising alternative to the metallic stent for heart valve applications where both resilience and adaptability are essential. Finally, 20% bismuth oxychloride was incorporated into the PCL / PLA (75:25) matrix to enhance stent radiopacity and enable better visualization and tracking during animal studies65. Re- evaluation of the stent's biocompatibility or hemocompatibility indicated that the inclusion of 20% bismuth oxychloride did not significantly alter the biocompatibility and hemocompatibility of the material, showing comparable behavior to PCL / PLA stent without the additive, and making it a viable option for further development in medical applications.

[0076] To demonstrate the functionality of the stent produced from the selected PCL / PLA (75:25) blend in vivo, transcatheter stent implantation studies were performed in a porcine model as described below. Three stents were successfully deployed in the pulmonary root and immediate and sustained performance were demonstrated for up to 5 hours. The three stents performed as expected after delivery without peri- or post-procedural complications. Post-mortem analyses revealed a thrombus-free smooth surface of the pulmonary artery and no endothelial cell damage, while the stent maintained its structural integrity, confirming the feasibility of implanting bioresorbable polymeric stents via minimally invasive procedures.

[0077] Polymer blend preparation

[0078] The Polycaprolactone powder (PCL, average Mn=80,000 g / mol, Sigma-Aldrich, USA) and polylactic acid granules (PLA, 3 mm nominal granule size, Sigma-Aldrich, USA), were mixed at PCL / PLA weight ratios of 100:0, 75:25, 50:50, 25:75, and 0:100, respectively, resulting in five samples containing PCL / PLA mixtures of different weight ratios (i.e. groups). Each of the samples was dissolved in 1 ,1 ,1 ,3,3,3-Hexafluoro-2-propanol (HFIP, Mw=168.04 g / mol, Sigma-Aldrich, USA) to obtain a final concentration of 60% (w / v). Then, 5% (w / w) of the Poly(L-lactide-co-caprolactone) compatibilizer (PLCL, lactide:caprolactone ratio of 35:65 (weight%, w / w), Sigma-Aldrich, USA), was added to the PCL / PLA mixture to decrease the phase separation, resulting in a PCL / PLA blend (termed "blend", in terms of a solution having a decreased phase separation; even if possibly not a homogenous blend F07418 03.12.2025

[0079] 15 yet). All samples of PCL / PLA blends were sonicated for 8 hours at room temperature to achieve respective homogenized PCL / PLA blends being homogenous and having a high viscosity. Each of the homogenized PCL / PLA blend samples was then poured into a mold and submitted to a heat treatment procedure at high pressure (2 bar) and high temperature (90°C) conditions for 24 hours, resulting in a precursor implant body. Finally, the samples were removed from the respective molds and cooled down at room temperature, resulting in a bioresorbable polymeric medical implant body. These samples were prepared for analysis and characterization purposes. For the purpose of subsequent use as implants, specifically designed molds are necessary, or the homogenized PCL / PLA blend can be used as an "ink" in a 3D printing process based on a selected implant design, as described below.

[0080] PCL / PLA blend characterization

[0081] 1 . Macroscopic and microscopic analysis:

[0082] Representative polymer sheet samples were evaluated macroscopically with a digital camera (Nikon, Japan) and microscopically by scanning electron microscopy (SEM) analysis. Briefly, polymer samples were frozen in liquid nitrogen, fractured with pliers, and platinum-sputtered (8 nm, CCU-010 HV Compact Coating Unit, Safematic GmbH). SEM preparation was performed at the Center for Microscopy and Image Analysis of the University of Zurich (Zurich, Switzerland). Pictures were acquired using a Zeiss GeminiSEM 450 with an acceleration voltage of 26 kV.

[0083] 2. Fourier-transform infrared spectroscopy (FTIR)

[0084] A FTIR spectroscope (Thermo Fischer Nicolet iS-50 FT-IR) was used to study the chemical structures of the PCL / PLA blend and the byproducts of the reaction between PCL, PLA, and the PCL-PLA copolymer. The prepared samples (three samples per PCL / PLA ratio) were ground into powder in a mortar and then mixed with potassium bromide (KBr) powder for testing. The mixture was pressed into a thin, transparent pellet using a hydraulic press and then placed in the sample holder of the FTIR spectroscope. The FTIR spectra were recorded in the range of 4000-400 cm-1at a resolution of 4 cm-1. Each sample was scanned multiple times to ensure reproducibility and accuracy. The resulting spectra were analyzed to identify characteristic absorption bands corresponding to the functional groups present in the samples.

[0085] 3. Differential scanning calorimetry (DSC)

[0086] DSC is a thermo-analytical technique in which the difference in the amount of heat required F07418 03.12.2025

[0087] 16 to increase the temperature of a sample and a reference is measured as a function of temperature. A Thermo Fischer Nicolet iS-50 was used to investigate the melt crystallization and glass transition behavior of the PCL / PLA samples (three samples per PCL / PLA ratio). After keeping the PCL / PLA samples at 25 °C for 10 min, the first heating scan was performed under heating from 25 to 300 °C at a speed of 15 °C / min. Subsequently, the samples were kept at 300 °C for 1 min and cooled down to room temperature at a speed of 5 °C / min to eliminate the thermal stress. The second heating scan was then performed under heating to 300 °C at a speed of 10 °C / min. The data from the second heating scan were recorded and analyzed using the accompanying software to determine the melt crystallization and glass transition behavior of the PCL / PLA samples.

[0088] 4. Mechanical tests

[0089] According to the ISO 527-3 standard, the mechanical properties of non-heated PCL / PLA blends not containing compatibilizer, and heat-treated homogenized PCL / PLA blends with compatibilizer were measured on a uniaxial tensile testing machine (Shimadzu AGS-X, Japan) equipped with a 100 N load cell (Shimadzu). Three samples per group were punched in dogbone-shapes with sizes recommended by the ISO 37 (type 4) standard. Samples were clamped at a distance of 5mm from their free edge and pulled at a displacement speed of 0.5 mm / min until failure. The force required to cause failure was measured, and the stress-strain data were recorded. From this data, the Young's modulus of the samples was calculated to evaluate their mechanical properties.

[0090] 5. Biocompatibility

[0091] The biocompatibility of the samples was evaluated with a cell proliferation assay31(MTT- assay, a calorimetric assay for assessing cell metabolic activity). Samples were cut into a disk shape with a diameter of 6mm and put in a 96-well plate. After sterilization with ethanol 70%, human dermal fibroblasts (hDFs) and human umbilical vein endothelial cells (HUVEC) were seeded on the samples (3 samples per group and cell line) at a density of 1 xio4cells / well, followed by incubation under the standard culturing conditions (37°C and 5% CO2 with saturating humidity) for 1 , 3, and 7 days. Samples were then washed three times with PBS and stained using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay (5 mg / ml) with cell culture medium and incubated for 4 hours. After incubation, the medium was removed and DMSO was added to dissolve the formed formazan crystals. The absorption value of each sample was read at 570 nm using a microplate reader (Infinite M1000 PRO, Tecan). F07418 03.12.2025

[0092] 17

[0093] 6. Thrombin generation

[0094] Thrombin generation was measured using a kit (Haemoscan) according to the manufacturer’s protocol. Plasma, along with test and reference materials, were incubated, and samples were collected at time points t = 1 , 2, 3, and 4 minutes. Subsequently, the optical density (OD) at 405 and 540 nm was measured for the samples. The thrombin concentration was determined from the calibration curve of OD405 values, where the thrombin concentration (mll / ml) was plotted against the incubation time.

[0095] 7. Biodegradability

[0096] To evaluate biodegradation properties, the heat-treated samples were immersed in PBS (15 ml) at 37 °C for 120 days and replaced weekly. Every month, the samples were removed, dried, and weighed. The following equation Eq.1 was used to calculate the weight loss percentage:

[0097] Weight loss (%) = ((W1-W2) / W1)x100 (Eq.1)

[0098] In the above equation Eq.1 , W1 represents the original dry weight of the sample and W2 indicates the final dry weight. In addition, 4 months after degradation, the mechanical properties of the degraded samples were evaluated by the mechanical tests mentioned above.

[0099] Polymeric stent 3D-printing

[0100] A 3D-printer with a single rotational axis was adopted for the polymeric heart valve stent fabrication32. Different stent designs were generated using Rhino (V7) software, and a mixture of PCL / PLA (75:25) was used to prepare a homogenized PCL / PLA blend as described above and used as ink. Beforehand, a custom-made polyvinyl alcohol (PVA) rotating mandrel was created using a fused deposition modelling (FDM) 3D-printer (see Fig. 1 A), which was subsequently fixed on the rotary axis of the 3D-printer and used as a mandrel / scaffold for the polymeric stent printing. The homogenized PCL / PLA blend ("ink") was poured into a syringe and located on top of the tubular 3D printer nozzle (D = 0.4 mm). After injection, the PVA rotating mandrel collected the homogenized PCL / PLA blend (ink / extrudate) shaping it in a selected stent design according to the pre-programmed G- Code (see Fig. 1 B and C) on the mandrel. Injecting the homogenized PCL / PLA blend via a syringe and through a nozzle onto the rotating mandrel allowed a circular polymer distribution. The micrometer nozzle diameter enabled printing stents with different strut dimensions. After printing, the stents were subjected to a heat treatment at a temperature of 90°C, at gradually increasing pressure (maximum of 2 bar) for 24 hours (see Fig. 1 D). Finally, the 3D-printed polymeric stent was cooled down to room temperature and the PVA F07418 03.12.2025

[0101] 18 mandrel was subsequently removed by dissolution in water (see Fig. 1 E). Three different types of stents were produced, namely according to a non-crimpable standard design, a crimpable zig-zag design, and a crimpable one cell design (as seen in Fig. 1 F from left to right; scale bar = 1cm).

[0102] Polymeric stent characterization

[0103] Biodegradability under dynamic conditions:

[0104] The biodegradation of polymeric stents was evaluated in a dynamic situation by keeping stents in a diastolic pulse duplicator bioreactor system. The prepared stents were soaked in PBS (250 ml) at 37°C in the bioreactor with a pressure of one bar (flow rate: 200 ml / min) and changed weekly for six months. Every month stents were taken out, dried, and weighed, and Eq. 1 was used to calculate the weight loss of the stents.

[0105] Mechanical tests:

[0106] The polymeric stents were divided into three groups (n=3 per group, non-crimpable standard design, crimpable one cell design, and crimpable zig-zag design (see Fig. 1 F)) plus a control nitinol stent. The mechanical properties of the stents were evaluated by doing a crush resistance to radially applied load (radial force) test based on the ISO 25539-2:2020 (D.5.3.4.3). For this purpose, each stent was placed unconstrained in a radial force compression chamber (Type RTA 124 Twin Cam Compression Station, Blockwise Engineering) and had time to adapt to the test temperature of 37°C. A compressive load was applied to the stent at a constant rate of 0,1 mm / s. The compression dies reduced the test chamber's diameter to 10 mm for crimpable stents and to 22 mm for non-crimpable stents, applying a uniform radial load to the stents. A dwell time of 5 seconds before opening was given. The total radial force was calculated using the following equation Eq.2: TRF= (2 / K) xF (Eq.2)

[0107] In Eq.2, TRF is the total radial force in N, K is the radial force tester proportionality constant, and F is the linear input load in N.

[0108] The radial load was calculated by using the following equation Eq.3: Radial load =TRF / stent length (Eq.3)

[0109] In Eq.3, the radial load is the radial force per length in N / mm, TRF is the total radial force in N, and stent length is the individual stent length in mm.

[0110] Animal study

[0111] Development of a radiopaque polymeric stent:

[0112] The PCL / PLA (75:25) blend ("ink") was mixed with 20% (w / v) bismuth oxychloride to F07418 03.12.2025

[0113] 19 implement radiopacity properties in a porcine model. Biocompatibility, Thrombin generation, dynamic biodegradation, and mechanical tests were repeated for the polymer blend (i.e. ink) formulation according to the previously described protocols.

[0114] Delivery device development and stent crimping:

[0115] To enable the transapical delivery of the polymeric stent, a custom-made delivery device was designed and manufactured using a Stereolithography (SLA) 3D printer (Fig. 2 A). The delivery device consisted of a PTFE valve housing of 18 mm diameter (Fig. 2 A, white) and a valve transferring tool (Fig. 2 A, brown), specifically developed to enable the final insertion of the crimped stent in the pulmonary artery. The crimper was used to reduce the stent's outer diameter from 84 Fr to 48 Fr (from 28 mm to 16 mm) and then it was pushed to the valve housing by the valve transferring tool (Fig. 2 B). The delivery device included a hole for the transcatheter wire, which allowed precise guidance under fluoroscopy (Fig. 2 C). No ballon inflation was necessary for deployment of the stent, it expanded autonomously, demonstrating its self-expandability in vivo.

[0116] In vivo implantation of polymeric stent:

[0117] The animal study was conducted at the Division of Surgical Research at the University Hospital of Zurich, ensuring that all animals received humane care following the "Principles of Laboratory Animal Care" and the "Guide for the Care and Use of Laboratory Animals" by the National Institutes of Health. The study protocols were approved by the Cantonal Veterinary Office (License number ZH_072_2023) and adhered to European Union guidelines (86 / 609 / EEC) and the Swiss Federal Animal Protection Law and Ordinance.

[0118] To evaluate the feasibility of transapical stent implantation and stent hemocompatibility, an in-vivo study was conducted on three female pigs selected (see table in Fig. 3). Before implantation, the pulmonary artery geometry and size were measured using fluoroscopy- guided angiography (ALLURA FD 20 / 20, Philips Electronics).

[0119] The animals underwent surgery through an anterolateral thoracic approach via the third intercostal space. Following mini-thoracotomy and pericardiotomy, the right ventricular apex was punctured using two purse-string sutures, and the delivery system was inserted under fluoroscopy. Baseline contrast angiography was performed to assess the native pulmonary artery, and after confirming the correct positioning of the device, the polymeric stent was deployed under fluoroscopic guidance.

[0120] The planned follow-up period for all animals (n = 3) was up to 3-5 hours post-implantation for the assessment of the technical feasibility of polymeric stent delivery and acute performance. Transesophageal echocardiography (TEE; Philips Healthcare iE33W F07418 03.12.2025

[0121] 20 xMATRIX Ultrasound) and angiography were performed immediately after deployment and before euthanasia. The study design did not include randomization or blinding.

[0122] Post-mortem evaluation:

[0123] Following euthanasia, the hearts of the respective animals were harvested, and the pulmonary artery and polymeric stent (n = 3) were examined macroscopically and microscopically with SEM to assess the stent's position and structural damage to the arterial wall. For the preparation of SEM samples, the following materials were utilized: conical containers, sodium cacodylate buffer (0.2 M, pH 7.4), 25% glutaraldehyde, Milli-Q water, ethanol solutions (70%, 80%, 95%, and 100%), and hexamethyldisilazane (HMDS). The fixation solution was prepared by mixing 1.5 ml of sodium cacodylate buffer, 0.3 ml of 25% glutaraldehyde, and 1.2 ml of Milli-Q water, and stored at 4°C. On Day 1 , the explant was washed with PBS and submerged in the fixation solution within a 50 ml conical container. On Day 2, the fixation solution was removed, and the sample was bisected. Samples underwent a dehydration process by sequentially submerging them in 70% ethanol for 1 hour and 30 minutes at 4°C, 80% ethanol for 1 hour at 4°C, 95% ethanol for 1 hour at 4°C, and 100% ethanol overnight at 4°C. On Day 3, the ethanol was refreshed with 100% ethanol for 1-2 hours at room temperature, followed by the addition of HMDS, just enough to submerge the flat sample. The HMDS was quickly pipetted off within 3 minutes to prevent remnants on the SEM scans. Finally, the samples were left open under a fume hood to allow the HMDS to evaporate completely.

[0124] For histology analysis, pulmonary arteries were fixed in 4% paraformaldehyde for 24 hours. The tissue sections were stained with hematoxylin and eosin (H&E) an CD31 for detailed analysis. In addition, stent samples were fixed for SEM in a buffer of 50% Sodium Cacodylate Buffer (0.2 M, Ph 7.4, Sigma-Aldrich, USA), 10% SEM-grade Glutaraldehyde (25%, Sigma-Aldrich, USA) and 40% ultrapure water for 24 hours. Afterwards, a range of dehydration steps with Ethanol was applied at 4°C; 70% EtOH for 1 ,5 hours, 80% EtOH for 1 hour, 95% EtOH for 1 hour, and 100 % EtOH for 12 hours. Subsequently, one more step of 100% EtOH for 1-2 hours and 3 minutes incubation in hexamethyldisilazane (Sigma- Aldrich, USA) was performed, and the remaining liquid was evaporated. Then, the stents were coated with 4 nm platinum and SEM images were taken according to the previously described protocols.

[0125] Polymer blend characterization

[0126] Macro- and microscopic morphology:

[0127] Sample surface morphology was characterized for the different PCL / PLA ratios without or F07418 03.12.2025

[0128] 21 with heat treatment, as well as with heat treatment in combination with the compatibilizer (see table in Fig.4). Sheet samples formed from the respective blends without compatibilizer and without exposure to heat treatment show the presence of air vesicles in all tested groups (see top line of table in Fig. 4). On the other hand, samples formed from the respective blends without compatibilizer, and only subjected to heat treatment (90°C with 2 bar air pressure) do not present air vesicles, however, a phenomenon of polymer phase separation is observed (see center line of table in Fig. 4). Finally, samples containing the compatibilizer PLCL and subjected to heat treatment do not present any air vesicles or sign of phase separation (see bottom line of table in Fig.4). Thus, the presence of the compatibilizer allows for a more homogeneous distribution of the polymer within the samples, thereby counteracting phase separation.

[0129] To further demonstrate the efficacy of the procedure, cross-sectional SEM images of the samples not containing compatibilizer, without and with heat treatment were taken (Fig. 5). Samples without heat treatment show the presence of air vesicles (see indent in Fig. 5A) and cracks (arrows in Fig. 5A) along the whole length of the sample, while the absence of air vesicles is demonstrated after successful heat treatment of the sample (Fig. 5B). Air vesicles introduce micro-defects that compromise the mechanical properties of the sample. The combined effect of the compatibilizer and heat treatment produced samples with a uniform structure which are free of air vesicles (bubbles).

[0130] Chemical composition, thermal and mechanical properties:

[0131] FTIR tests for pure PCL show absorption peaks of 1726 cm-1 (C=O), 962 cm-1 (C-O-C), 1048 cm-1 (C-O-C), 1166 cm-1 (C-O-C), and 1367 cm-1 (-CH) (Fig. 6A). For pure PLA, the infrared absorption peaks of different functional groups appear at 1750 cm-1 (C=O), 875 cm-1 (C-O-C), 1046 cm-1 (C-O-C), 1131 cm-1 (C-O-C), 1353 cm-1 (-CH), and 1450 cm-1 (-CH3) (Fig. 6A). The curves for the blend of PCL / PLA clearly show that the infrared absorption peaks comprise a combination of the peaks of pure PCL and PLA (Fig. 6A). The absence of new characteristic peaks indicates that no chemical reactions occur among PCL, PLA, and PLCL.

[0132] The addition of PCL to PLA also affects the thermal properties of the final product. The DSC tests (differential scanning calorimetry) were performed for the different PCL / PLA blends, thereby providing the glass transition temperature (Tg) and the melting point (Tm) of the PCL / PLA blend (Fig. 6 B). The tests showed that all composites have two peaks, wherein the left one belongs to the composites' Tg, which also represents the melting point of PCL. The second peak is the Tm of the composites, which also represents the melting point of PLA. F07418 03.12.2025

[0133] 22

[0134] Young's modulus (E) is a material property representing the stretch and deformation capacity of a sample upon its spatial displacement and is defined as the ratio of tensile stress (o) to tensile strain (E). The Young's modulus of samples without the compatibilizer and without heat treatment, with only heat treatment, and samples with both the PLCL compatibilizer and heat treatment was tested for different ratios / concentrations of PCL and PLA (see table in Fig. 7). The results indicate that heat treatment in combination with the compatibilizer leads to an increase in the Young's modulus as the concentration of PLA increases. The values shown in the lowest line of the table reflect the Young's modulus displayed by the respective sample which underwent heat treatment in combination with the compatibilizer after 4 months of biodegradation in PBS.

[0135] Biocompatibility, biodegradation, and thrombin generation:

[0136] The biocompatibility of the different PCL / PLA blend samples was evaluated using an MTT assay using hDFs and HLIVECs as cell sources (Fig. 8). The results demonstrate that both cell types are able to adhere and proliferate in all tested samples (Fig. 8 A and B), showing increased absorbance values overtime, thus confirming the biocompatibility of the samples. The biodegradation of the respective samples was measured over four months the weight loss percentage of different PCL / PLA blends was plotted (Fig. 8C). The data indicate that the degradation rate increases with a higher proportion of PLA in the composite. Specifically, after four months, the PLA-only samples (0:100 PCL / PLA ratio) exhibit a weight loss of approximately 23%, while the PCL-only samples (100:0 PCL / PLA ratio) show a weight loss of about 20%. The degradation process is relatively slow during the initial two months for all groups. However, a noticeable acceleration in the degradation rate is observed after the two-month mark, particularly in the PLA group and those samples prepared from a PCL / PLA blend of higher PLA content, such as the PCL / PLA blends with a PCL / PLA weight ratio of 25:75 and 0:100. For instance, the samples prepared from a 50:50 PCL / PLA blend demonstrated a weight loss of around 12% by the fourth month, whereas the samples prepared from a 75:25 PCL / PLA blend exhibited a weight loss of approximately 18% (see Fig. 9).

[0137] After four months of degradation, the mechanical properties of the samples were evaluated (Fig.7). The results indicate that samples with higher amounts of PLA experienced a more rapid loss of mechanical properties during degradation. Notably, the last two groups (with the highest PLA content) became very brittle and weak, breaking before mechanical testing could be completed, thus there is no data in the two last columns. Despite the overall decrease in mechanical properties due to degradation, the material retained sufficient stiffness to maintain functionality after four months. This demonstrates that while higher F07418 03.12.2025

[0138] 23

[0139] PLA content accelerates degradation, the blends still possess enough mechanical integrity to be considered for applications such as bioresorbable stents.

[0140] To evaluate the hemocompatibility of the samples, thrombin generation levels were measured in plasma incubated with the test samples and reference materials in a thrombin generation assay (TGA). The results indicate that the maximum thrombin generation for the samples produced from PCL-only ("PCL"), PCL / PLA (75:25), and PLA-only ("PLA") blends are significantly lower than that of Medical Steel (MS), which is known to be highly reactive (Fig. 8D). Specifically, the maximum thrombin generation for these polymer samples is comparable to that of low-density polyethylene (LDPE), which is minimally reactive, and polymethylsiloxane (PDMS), which exhibits intermediate reactivity. These findings suggest that the samples produced from PCL-only, PCL / PLA (75:25), and PLA-only blends have excellent hemocompatibility, making them suitable for biomedical applications where minimal blood clotting is crucial.

[0141] Based on the provided results, the PCL / PLA (75:25) blend was selected for further analyses and the fabrication of polymeric stents by 3D printing, as it provided an optimal balance of mechanical properties, biocompatibility, biodegradation rate, and hemocompatibility.

[0142] Polymeric stent characterization

[0143] Biodegradability under dynamic conditions:

[0144] Results report a relatively low stent biodegradation during the first three months of dynamic conditioning (Fig. 9), with a weight loss of 1%, for a stent formed from a PCL / PLA blend comprising a PCL / PLA weight ratio of 75:25. This low degradation profile suggests a minimal impact on the mechanical properties of the stent. However, the degradation rate accelerates after the fourth month of exposure to dynamic conditioning. Here, the stents show a weight loss of approximately 2%, which trend constantly continued, experiencing 3% and 4% weight loss by the fifth and sixth month, respectively. These observations showed higher degradation in the presence of bismuth oxychloride (BiCIO 20%). However, the addition of BiCIO 20% was necessary to reach a comparable radiopacity / visibility during and after implantation, as for standard metallic stents.

[0145] Mechanical properties:

[0146] The load and deformation characteristics of the stents under application of a circumferentially uniform radial load was evaluated in a crimping test. The results provide a comprehensive comparison of the mechanical properties of different stent designs, including standard polymeric stents, one-cell stents, zig-zag stents, and standard metallic stents (table in Fig.10). The standard polymeric stent has robust mechanical properties and F07418 03.12.2025

[0147] 24 the maximum crimpability is 2.7mm (first diameter minus diameter at max. TRF). The TRF results of the one-cell stent showed that it can endure higher forces and is crimpable by 15mm. The zig-zag stent, while showing a slightly lower maximum TRF compared to the one-cell stent, still exhibited strong mechanical properties. So, the study was continued with a stent with a zig-zag design.

[0148] In vivo results

[0149] Radiopaque polymeric stent characterization:

[0150] The visibility of polymeric stents with varying concentrations of bismuth oxychloride (BiCIO) were compared to a metallic stent (not illustrated). The fluoroscopy images indicated that polymeric stents with 20% BiCIO approach the reference radiopacity levels of a metallic stent, making them suitable for clinical applications where visibility under imaging is crucial. The results of the biocompatibility and hemocompatibility tests for the stent incorporating PCL / PLA (75:25) with 20% BiCIO are presented in Fig. 11 and 12, respectively). The biocompatibility assessment, measured by an MTT assay (Fig. 11), demonstrates that the addition of BiCIO does not induce cytotoxicity, as indicated by the comparable absorbance values between the stent material and the control group. In terms of hemocompatibility, the thrombin generation test (Fig. 12) shows that the PCL / PLA (75:25) stent with 20% BiCIO generates significantly lower thrombin levels compared to Medical Steel (MS), a highly reactive material often used as a benchmark in such tests. This indicates that the stent material has a low potential for inducing blood clot formation, making it hemocompatible and suitable for hollow organ applications, especially in cardiovascular environments.

[0151] The results provide a detailed analysis of the mechanical performance of the zig-zag stent containing 20% BiCIO is shown in Fig.13. The initial diameter of the stent was recorded as 27.03 mm. Under the application of radial force, the stent reached a maximum TRF of 105.9 N. The diameter at this maximum radial load was reduced to 16 mm. This data suggests that the zig-zag stent containing BiCIO 20% and produced from a PCL / PLA (75:25) blend maintains its structural integrity effectively under significant radial compression, making it a suitable candidate for continued study and potential application.

[0152] In vivo performance of polymeric heart valve stent and post-mortem evaluation:

[0153] To assess the feasibility and safety of the polymeric heart valve stent, three stents (n = 3) with a zig-zag design and produced from a PCL / PLA (75:25) blend were successfully crimped, loaded into the delivery device and implanted transapically (not shown). Contrast angiography confirmed accurate stent positioning within the native pulmonary artery (not shown) of the respective pigs. Both two-dimensional (2D) and three-dimensional (3D) F07418 03.12.2025

[0154] 25 echocardiographic assessments demonstrated sustained stent performance (not shown). The evaluation revealed no signs of stenosis, and the stents remained securely anchored in all animals. Additionally, there were no postoperative complications, such as embolization or thrombosis. Following the planned follow-up period of 3 to 5 hours, the animals were euthanized, and the polymeric stents, along with the pulmonary artery, were harvested for post-mortem analysis.

[0155] Macroscopic and microscopic evaluation:

[0156] The animals were euthanized 3-5 hours post-implantation, and their hearts were harvested for further analysis. Macroscopic examination confirmed the presence of the stent within the pulmonary artery and no sign of damage. Histology and SEM analysis were employed to assess the stent's interaction with the arterial wall at a microstructural level (not illustrated). H&E and CD31 staining confirmed a thrombus-free smooth surface and retained tissue morphology with the absence of damages to the endothelial layer of the pulmonary artery. The SEM images revealed that the stent maintained its structural integrity and was well- apposed to the arterial wall. No significant signs of damage, such as thrombosis, were observed in the analysis of pulmonary artery tissue.

[0157] Conclusion:

[0158] The abovementioned study successfully developed and validated a novel self-expandable, bioresorbable polymeric heart valve stent designed for use with minimally invasive transcatheter technologies. By employing a composite of PCL and PLA, most preferably a PCL / PLA (75:25) blend, the stent formed therefrom is crimpable while demonstrating a favorable combination of mechanical strength, biodegradability, biocompatibility, and hemocompatibility. So far, no crimpable polymeric stents suitable for medical applications have been described. Comprehensive in vitro testing revealed that the material’s mechanical properties were sufficient to provide temporary structural support, while its degradation profile aligns well with the requirements for gradual tissue integration. Biocompatibility and hemocompatibility tests confirmed that the composite material elicited minimal inflammatory responses, demonstrating the potential for safe interaction with blood and tissue in a clinical setting. The fabrication of the stent using a custom-built 3D-printer with a single rotational axis, along with the development of a 3D-printed delivery device, highlights significant advancements in the precision and efficiency of bioresorbable stent production. This approach allows for the fine-tuning of stent dimensions and properties, offering solutions to meet specific clinical requirements.

[0159] The deployment of the stent in an porcine model provided critical in vivo validation, F07418 03.12.2025

[0160] 26 demonstrating safe and effective deployment.

[0161] These findings indicate that bioresorbable polymeric stents provide a promising alternative to traditional metallic stents, particularly in applications requiring adaptability, such as pediatric heart valve replacement, where growth and remodeling capacities are essential. Future research should focus on conducting long-term in vivo studies to evaluate the degradation process, tissue remodeling, and functional integration of the valve over extended periods. The development of next-generation bioresorbable stents may also benefit from optimizing polymer compositions and exploring advanced 3D printing techniques to further enhance mechanical properties and customization.

[0162] F07418 03.12.2025

[0163] 27

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Claims

F07418 03.12.202531CLAIMS1. Method for manufacturing a bioresorbable polymeric medical implant, preferably a stent, more preferably a vascular, valvular, or tracheal stent, most preferably a cardiovascular stent, such as a heart valve stent, comprising the following steps: a.) mixing of PCL and PLA, at a PCL / PLA weight ratio in a range of from 60:40 to 85:15, preferably in a range of from 70:30 to 80:20, more preferably at a PCL / PLA weight ratio of 75:25, resulting in a PCL / PLA mixture, wherein preferably, the PCL / PLA mixture contains PCL in powder form and PLA in granular form; b.) dissolving the PCL / PLA mixture resulting from step a.) in a solvent, resulting in a PCL / PLA solution, wherein the solvent preferably is selected from a group consisting of 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (HFIP), trifluoroethanol (TFE), dimethyl sulfoxide (DMSO), dichloromethane (DCM), and chloroform, wherein the solvent more preferably is HFIP; c.) adding a compatibilizer to the PCL / PLA solution resulting from step b.), resulting in a PCL / PLA blend, wherein the compatibilizer is preferably added at a concentration in a range of 3-8% (w / w), more preferably of 4-7% (w / w), most preferably at a concentration of about 5% (w / w) with respect to the weight of the PCL / PLA mixture, wherein preferably the compatibilizer is a PCL / PLA copolymer, preferably comprising a lactide:caprolactone ratio in the range of from 15:85 to 40:60, more preferably of 30:70, most preferably of 35:65 (w / w), wherein the compatibilizer most preferably is poly(L-lactide-co- caprolactone) (PLCL); d.) agitating the PCL / PLA blend resulting from step c.), preferably by sonication, resulting in a homogenized PCL / PLA blend; e.) forming the homogenized PCL / PLA blend to a precursor implant body according to a selected implant design, resulting in a precursor implant body; f.) submitting the precursor implant body resulting from step e.) to a heat treatment at 60-120°C at a pressure exceeding atmospheric pressure, resulting in a dried implant body; g.) cooling of the dried implant body resulting from step f.), preferably at least to room temperature, resulting in a bioresorbable polymeric medical implant.F07418 03.12.2025322. Method according to claim 1 for manufacturing a biodegradable polymeric medical implant, characterized in that in step e.), the precursor implant body is formed by using the homogenized PCL / PLA blend as an ink in a 3D printing process based on the selected implant design, wherein preferably, the precursor implant body is formed by depositing the homogenized PCL / PLA blend on a rotating mandrel which serves as a removable scaffold for the precursor implant body.

3. Method according to one of claims 1-2 for manufacturing a polymeric medical implant, characterized in that in step f.), the heat treatment is carried out at 80-100°C, preferably at about 90°C, and preferably at 1-3 bar, more preferably at 1.5-2.5 bar, most preferably at about 2 bar, wherein preferably the heat treatment is carried out for 8-30 hours, preferably for 12-24 hours.

4. Bioresorbable polymeric medical implant, preferably a vascular, or valvular or tracheal stent, most preferably a cardiovascular stent, such as a heart valve stent, manufactured by a method according to one of claims 1-3.

5. Polymer composition, for use in the manufacture of a bioresorbable polymeric medical implant, comprising a solution containing a mixture of polycaprolactone (PCL) and polylactic acid (PLA), the polymer composition further comprising a compatibilizer, characterized in that a PCL / PLA weight ratio in the PCL / PLA mixture is in a range of from 60:40 to 85:15, and that the compatibilizer is contained in the polymer composition at a concentration of less than 10% (w / w) with respect to the weight of the PCL / PLA mixture.

6. Polymer composition according to claim 5, characterized in that the PCL / PLA weight ratio is in a range of from 70:30 to 80:20, wherein the PCL / PLA weight ratio preferably is 75:25.

7. Polymer composition according to one of claims 5-6, characterized in that the concentration of the PCL / PLA mixture in the solution is in a range of 40-80% (w / v), preferably of 50-70% (w / v), more preferably of 55-65% (w / v), and that the concentration of the PCL / PLA mixture in the solution most preferably is about 60% (w / v).F07418 03.12.2025338. Polymer composition according to one of claims 5-7, characterized in that the solvent is selected from a group consisting of 1 ,1 , 1 ,3,3, 3-hexafluoro-2- propanol (HFIP), trifluoroethanol (TFE), dimethyl sulfoxide (DMSO), dichloromethane (DCM), and chloroform, wherein the solvent preferably is HFIP.

9. Polymer composition according to one of claims 5-8, characterized in that the compatibilizer is a PCL / PLA copolymer, preferably poly(L-lactide-co- caprolactone) (PLCL), preferably comprising a lactide: caprolactone ratio in the range of from 15:85 to 40:60, more preferably of 30:70, most preferably of 35:65 (%w / w).

10. Polymer composition according to one of claims 5-9, characterized in that the compatibilizer is contained in the polymer composition at a concentration of 3-8% (w / w), preferably of 4-7% (w / w), more preferably of 4.5-6% (w / w), most preferably of about 5% (w / w) with respect to the weight of the PCL / PLA mixture.11 . Method for producing a polymer composition suitable for the manufacture of a bioresorbable polymeric medical implant, comprising the following steps: a.) mixing of PCL and PLA, at a PCL / PLA weight ratio in a range of from 60:40 to 85:15, preferably in a range of from 70:30 to 80:20, more preferably at a PCL / PLA weight ratio of 75:25, resulting in a PCL / PLA mixture, wherein preferably, the PCL / PLA mixture contains PCL in powder form and PLA in granular form; b.) dissolving the PCL / PLA mixture resulting from step a.) in a solvent, resulting in a PCL / PLA solution, wherein the solvent is preferably selected from a group consisting of 1 ,1 ,1 ,3,3,3-hexafluoro-2-propanol (HFIP), trifluoroethanol (TFE), dimethyl sulfoxide (DMSO), dichloromethane (DCM), and chloroform, wherein the solvent most preferably is HFIP; wherein preferably the solvent is added up to a concentration of 40-80% (w / v), more preferably up to a concentration of 50-70% (w / v), most preferably up to a concentration of about 60% (w / v) of the PCL / PLA mixture in the PCL / PLA solution; c.) adding a compatibilizer to the PCL / PLA solution resulting from step b.), resulting in a PCL / PLA blend; wherein the compatibilizer isF07418 03.12.202534 preferably added at a concentration in a range of 3-8% (w / w), more preferably of 4-7% (w / w), most preferably at a concentration of about 5% (w / w) with respect to the weight of the PCL / PLA mixture, wherein preferably the compatibilizer is a PCL / PLA copolymer preferably comprising a lactide: caprolactone ratio in the range of from 15:85 to 40:60, more preferably of 30:70, most preferably of 35:65 (w / w), wherein the compatibilizer most preferably is poly(L-lactide-co-caprolactone) (PLCL); d.) agitating the PCL / PLA blend resulting from step c.), resulting in a homogenized PCL / PLA blend, wherein preferably the agitation is carried out by sonication, preferably at a power of 20W and a frequency of 20 kHz.

12. Polymer composition suitable for the manufacture of a bioresorbable polymeric medical implant, preferably of a stent, wherein the polymer composition is obtained by a method according to claim 11.

13. Polymer composition according to one of claims 5-10, preferably obtained by a method according to claim 11 , for use in the manufacturing of a bioresorbable polymeric medical implant, for use as an ink for 3D-printing of the bioresorbable polymeric medical implant, or as an injection molding substrate, a spinning substrate, or a dip-coating substrate in the manufacturing of the bioresorbable polymeric medical implant.

14. Use of the polymer composition according to one of claims 5-10, preferably obtained by a method according to claim 11 , as an ink in a 3D-printing process of a bioresorbable polymeric medical implant, or as an injection molding-, a spinning-, or a dip-coating substrate for the manufacture of a bioresorbable polymeric medical implant.

15. Bioresorbable polymeric medical implant, preferably a stent, more preferably a vascular, valvular or tracheal stent, most preferably a cardiovascular stent, such as a heart valve stent or a venous valve stent, formed from the polymer composition according to one of claims 5-10, preferably formed from the polymer composition obtained by a method according to claim 11.

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